White matter (WM) comprises about half of the brain (the other being the gray matter, GM), and is composed of bundles of myelinated nerve cell processes that connect various brain regions to each other. WM dysfunction is implicated in a number of neurological diseases such as Alzheimer's Disease, multiple sclerosis, and brain injury. At present, diagnostic and mechanistic studies of WM diseases primarily rely on structural imaging techniques such as T2-weighted image and Diffusion Tensor Imaging (DTI). Physiologic changes usually takes place before structure is altered, thus imaging of related parameters such as vascular physiology may provide an early marker for disease diagnosis and progression. While vascular physiology in the GM has been studied for more than a century, little is known about vascular physiology in the WM. Although it is intuitive to expect that WM perfusion should follow principles similar to those for the GM except that everything is smaller in amplitude (because WM contains 70-75% less vasculature compared to GM), several lines of evidence suggest that some important differences exist. The goal of the present study is to elucidate distinctive features of perfusion in the WM, in comparison to that in the GM. As an initial application, we will also characterize age-related changes in WM blood supply, which will allow us to test whether structural changes in WM with age can be attributed to a lack of blood supply. The proposed work was motivated by several surprising findings made by our group and others. The PI's lab was the first to show that WM CBF can be measured on a tract-by-tract basis and that fiber tracts with higher CBF paradoxically had a lower FA in water diffusion. We also showed an interesting finding that WM CBF may increase with age, while GM CBF in the same cohort decreased with age. Finally, although GM CBF is augmented by inhalation of CO2, our preliminary studies suggested that WM CBF stayed unchanged or even slightly decreased by this maneuver. A working hypothesis that may explain all of the above observations is that mechanical properties of WM such as tightness of the fiber bundle may have a major influence on WM blood supply. Blood vessels in a tighter bundle have less capacity to expand and result in lower CBF and CBV. This project has three Specific Aims. Aim 1: Determine spatial distribution of WM CBF and CBV at the level of individual fiber tracts and examine their relationship with DTI parameters. Aim 2: Examine how WM CBF and CBV respond to vascular challenges and how the responses are different from those in the GM. Aim 3: Characterize age-related differences in WM vascular parameters. The present study serves as the first step to unravel the mechanism of blood supply in the WM. By demonstrating that WM vascular parameters can be determined reliably using state-of-the-art imaging methods and elucidating how blood supply is distributed and controlled in healthy WM, this study may open new avenues for future research of WM diseases. PUBLIC HEALTH RELEVANCE: Blood supply to one type of brain tissue called white matter is poorly understood and may be critical in several brain diseases such as Alzheimer's Disease, multiple sclerosis, and brain injury. The present study aims to improving our understanding of this phenomenon by measuring a comprehensive set of vascular parameters using non-invasive MR imaging technologies. This study will also investigate how blood supply in older individuals may be different from that in young participants.